As one of the most serious complications of diabetes mellitus, diabetic retinopathy is a major cause of blindness all over the world. In fact, diabetic retinopathy occurs in about 4.4 million of the estimated 11 million persons with diabetes in the United States. Every year approximately 4,700 of these patients become blind. In light of current prolonged survival rates for diabetic patients coupled with an increased likelihood of retinopathy in long term diabetics, the incidence of retinopathy can only be expected to increase in the future.
In spite of the wide clinical variation of the different stages of diabetic retinopathy, there are generally three processes that are known or thought to be a pathogenetic importance. The first is usually characterized by microangiopathy, ischemia and hypoxia. Visible signs of this process include capillary obliteration or nonperfusion, arteriolar-venular shunt, hyperaggregation of red cells and platelets, sluggish blood flow and an impaired ability of red cells to release oxygen. The second process involves abnormal metabolism of carbohydrate, protein and arachidonic acid.
The third process of diabetic retinopathy is thought to involve lipid peroxidation of the retinal membrane, possibly oxygen radical-induced. Studies have shown that the lipid peroxidation product (malondialdehyde) level in a diabetic patient's blood plasma is significantly higher than that of normal subjects. H. Kaji et al., "Increased Lipoperoxide Value and Gutathione Peroxidase Activity of Type 2 (Non-Insulin Dependent) Diabetic Women," Klin. Wochenschr., 63, 765-768 (1985). Moreover, it has been found that the retina is particularly susceptible to damage by oxygen. C. H. Chen and A. Patz, "Component of Vitreous-Soluble Protein, Effect of Hyperoxia and Age," Invest. Opthalmal., 15, 228-232 (1976). Lipid peroxidation of the retinal membrane may also be caused by exposure to ultraviolet radiation. H. Pasantes-Morales and C. Cruz, "Taurine and Hyptaurine Inhibit Light-Induced Lipid Peroxidation and Protect Rod Outer Segment Structure," Brain Res., 330, 154-154 (1985). Although many of these characteristics of diabetic retinopathy are known, effective prevention and therapy for this disease is not available.
Senile macular degeneration, associated with aging and drusen, is the leading cause of severe visual loss in the United States and Western Europe in persons aged 55 years or older. It is of unknown cause, and no treatment has been shown to be of benefit to the majority of people who have nonexulative disease. Although drusen are the ophthalmoscopic hallmark of macular degeneration, the primary lesion appears to be in the retinal pigment epithelium (RPE). R. W. Young, Surv. Ophthalmol., 31, 291 (1987) relates macular degeneration to the gradual accumulation of lipofuscin in RPE cells, which is in turn thought to be related to photoxidative damage mechanisms. Therefore, the RPE may have a particular vulnerability to lipofuscin accumulation because of the normal daily phagucytic load of membranes rich in polyunsaturated acids, combined with the high-oxygen environment and the lifelong potential for light-induced free radical damage in the cells. See J. J. Weiter, Arch. Ophthalmol., 106, 183 (1988).
Anisodamine (6(s)-hydroxyhyoscyamine) is an alkaloid isolated from Anisodus tanguticus (solanaceae), a Chinese herb plant. Its chemical structure is only slightly different from that of atropine in that it possesses an hydroxy group on the sixth position of the tropane radical as shown in formula I: ##STR1##
In numerous medical studies, anisodamine has been identified as an anticholingeric agent and a vasodilator, with a weaker, and less toxic, effect than atropine.
In view of its ability to enhance microcirculation, anisodamine has been used in China since 1965 for treating many diseases including septic shock, severe lobar pneumonia, pancreatitis, central serous retinochoroiditis and myopia. See generally C. P. Li, Chinese Herbal Medicine. A publication of the John E. Fogarty International Center for Advanced Study in the Health Sciences, U.S. Department of Health, Education and Welfare, Public Health Service, NIH, DHEW Publication No. 75-732 pp. 11-20 (1974); "Anisodamine in the Treatment of Some Diseases with Manifestations of Acute Microcirculatory Insufficiency," Chinese Medical Journal, 1, 127-132 (March 1975). However, a further need exists for the development of new anisodamine-based treatments.